Altered proteoglycan metabolism has been implicated in a number of conditions including cardiac fibrosis, kidney disease, Pseudoxanthoma elasticum (PXE) and regenerative failure and poor recovery in the injured or diseased nervous system. PXE is a systemic degenerative disorder of connective tissue characterised by progressive mineralisation and fragmentation of elastic fibres and increased deposition of proteoglycans. These alterations in the extracellular matrix lead to a loss of elasticity in the skin, the eyes, and the cardiovascular system. PXE severity is associated with certain variations of XT-II, and it has been shown that overall xylosyltransferase activity is elevated in patients with certain variations of XT-I.
Cardiac fibrosis is a process that is characterized by a massive remodeling of the myocardial extracellular matrix (ECM) and the subsequent substitution of the functional tissue by inelastic fibrotic tissue. These alterations lead to an impaired organ function and finally to chronic heart failure. Up-regulation of proteoglycan expression is a main characteristic for the progression of this myocardial failure. During the fibrotic remodeling of the ventricular tissue, increased levels of the proteoglycans decorin and biglycan were found, confirming the importance of these matrix components in this process
The absence of axonal regeneration after spinal cord injury (SCI) has been attributed in part to the nonpermissive environment of the glial scar (Fawcett and Asher 1999). Although macrophages, microglia oligodendrocytes, invading Schwann cells and meningeal fibroblasts contribute to the glial scar, astrocytes predominate (Fawcett and Asher 1999). Reactive astrocytes in the injured CNS are heterogeneous with respect to their production of scar proteins (Fitch and Silver 1997). Whereas in the majority of cases the extracellular matrix molecules (ECM) produced by astrocytes have been shown to inhibit axonal regeneration (Bahr et al. 1995; Davies et al. 1999; McKeon et al. 1991; Reier and Houle 1988), astrocytes also have been shown to secrete ECM molecules that promote axonal growth (McKeon et al. 1991). Thus, astrocytes may promote or inhibit regeneration after SCI depending upon the balance of growth-inhibiting and growth-promoting ECM molecules that they produce.
Chondroitin sulfate proteoglycans (CSPGs) are probably the most important of the inhibitory molecules produced by reactive astrocytes (Eddleston and Mucke 1993; Fawcett and Asher 1999). In vivo and in vitro studies have shown that regenerating axons cease to extend their axons into areas rich in CSPGs (Davies et al. 1997; Davies et al. 1999; McKeon et al. 1991; Zuo et al. 1998). CSPGs share a common structure comprising a central core protein with a number of chondroitin sulfate side chains (Morgenstern et al. 2002). Chondroitin sulfate side chain synthesis is initiated by the addition of xylose onto a serine moiety of the core protein. This function is carried out by the enzyme xylosyltransferase (XT) that exists in two isoforms encoded by two different genes XT-I and XT-II (Gotting et al. 2000). These side chains are subsequently sulfated by either chondroitin 4-sulfotransferase (C4ST) (Yamauchi et al. 2000) or chondroitin 6-sulfotransferase (Fukuta et al. 1995) although in astrocytes C4ST predominates (Gallo and Bertolotto 1990).
Astrocytes can also produce an array of growth promoting molecules including laminin (Liesi and Silver 1988), N-cadherin (Tomaselli et al. 1988), Neural cell adhesion molecule (NCAM) (Neugebauer et al. 1988) and fibronectin (Matthiessen et al. 1989). Using in vitro models of axon growth, laminin and fibronectin have been shown to be good substrates for neurite extension (Costa et al. 2002; Fok-Seang et al. 1995; Hammarback et al. 1988; McKeon et al. 1991; Rogers et al. 1983; Rogers et al. 1987). In vivo models demonstrate that sensory axon regeneration is dependent on astrocyte-associated fibronectin (Davies et al. 1997; Davies et al. 1999; Tom et al. 2004) and that intrathecal administration of laminin-γ1 promotes regeneration in a rat model of SCI (Wiksten et al. 2004).
It would be desirable to identify pathways and factors that differentially regulate the expression of growth-inhibiting molecules such as proteoglycans and growth-promoting molecules such as laminin and fibronectin in order to develop therapies for diseases and other conditions associated with the up-regulation of growth-inhibiting molecules and/or down-regulation of growth-promoting molecules.